Sage Journals: Discover world-class research

Abstract

Objectives:

The spectrum of metabolic disease, including obesity, prediabetes and Type 2 diabetes mellitus (T2DM), is increasing globally at an alarming rate. In addition to the vascular complications classically associated with diabetes, other ‘non-classical’ comorbidities like psychological distress, osteoporosis and sarcopenia are getting increasingly reported with diabetes. Hypogonadism in males has been reported to be associated with diabetes from the early 1990s. Around one-fourth of male subjects with diabetes mellitus were found to have decreased testosterone levels by several studies from both India and other countries. There is apparently a bidirectional link between T2DM and hypogonadism, with each contributing to and adversely affecting the other. This article briefly reviews the literature related to diabetes and hypogonadism, including the burden in an Indian setting, the pathophysiological link between the two, clinical evaluation and the evidence for and against testosterone replacement therapy.

Methodology:

Literature and information regarding this topic were collected from various original articles, review articles, systematic reviews and meta-analyses available on various platforms such as Google Scholar and PubMed.

Results:

The caveat here for clinicians is whether this low testosterone in a diabetic male who is more than 50 years old is due to late-onset hypogonadism (andropause) or is it a consequence per se due to diabetes. Physicians should remind themselves that a diabetic patient may also harbour other conditions directly leading to hypogonadism (like hypothalamo-pituitary lesions or primary testicular conditions). Thus, it is imperative that a thorough history and physical examination are mandatory in all diabetes suspected to have hypogonadism. Judicious use of relevant hormonal tests, including FSH, LH, testosterone and sex hormone binding globulin (SHBG), may be warranted to confirm hypogonadism.

Conclusions:

Appropriate referral to endocrine specialists for further endocrine evaluation of aetiology and management may be required in a subset of patients. In these patients with diabetes with a clear organic aetiology of hypogonadism, the latter is managed with testosterone replacement at age-appropriate doses. However, in the larger group of diabetes patients with functional hypogonadism with or without symptoms of androgen deficiency, testosterone replacement therapy is controversial. There are studies that show improvement in metabolic metrics of body composition, glucose, lipid and inflammatory parameters. However, the main concern of aggravating an underlying androgen-dependent occult malignancy (prostate), rise in haematocrit-related potential thrombotic tendencies, including cardio- and cerebrovascular events, is to be weighed against the potential benefits. Thus, the Endocrine Society guidelines currently recommend against testosterone treatment for improving the metabolic status (glucose levels, dyslipidaemia) alone in a diabetic patient. However, the Indian consensus (Integrated Diabetes and Endocrine Academy [IDEA] group) suggests individualising testosterone replacement after discussing it with the patient.

Keywords

Ethnicity race religion women studies

Introduction

Hypogonadism is defined as a syndrome due to inability of the testicular tissue to produce normal physiological levels of testosterone with or without defective spermatogenesis.^[1] Generally, in routine clinical practice, normal testosterone secretion with isolated germ cell dysfunction is not considered equivalent to hypogonadism. From the causal point of view, hypogonadism may be due to defective hypothalamo-pituitary signalling to the testis (secondary hypogonadism) or due to testicular dysfunction (primary hypogonadism).^[2] The incidence of diabetes and obesity are rising at epidemic proportions, and India probably has the dubious distinction of being called as ‘diabetes capital’ of the world.^[3] Diabetes is directly linked with erectile dysfunction (ED), and the latter may be due to testosterone deficiency in at least in a small but significant proportion of those patients. In addition, after the fifth or sixth decade, testosterone levels may physiologically decline and is usually considered as andropause or late onset hypogonadism. In this background, many studies have demonstrated a significant association between hypogonadism and the spectrum of metabolic syndrome, namely central obesity, prediabetes and Type 2 diabetes mellitus (T2DM). Approximately 30% of diabetic patients are found to have low testosterone concentrations.^[4] Testosterone levels correlate inversely with body mass index (BMI) and insulin resistance but usually have no correlation with the degree or duration of hyperglycaemia.^[5,6] A potentially addressable and treatable condition like hypogonadism and diabetes has major implications in terms of increased cardiovascular (CV) risk factors and resultant increase in mortality. This review is an attempt to briefly review the current data and literature on hypogonadism and its relationship with diabetes.

Epidemiology

In the early 1990s, low testosterone concentrations were described in patients with T2DM [Table 1].^[7] Further studies revealed a structurally normal testis and hypothalamo-pituitary-gonadal (HPG) axis in these patients. This led to the hypotheses of a functional hypogonadotropic hypogonadism in this setting.^[8] Studies over the last few years have clearly established that at least one-fourth of men with T2DM have subnormal free testosterone (Free T) concentrations with inappropriately low to normal FSH and LH levels.^[9] Another 4% have low testosterone levels with elevated FSH and LH concentrations.^[10]

Various Indian studies have assessed the percent prevalence of hypogonadism in subjects with T2DM [Table 1]. In a study by Kumar et al it was found that testosterone levels were low in 70% men with moderate ED and 97% men with severe ED and coexisting diabetes.^[11] Similarly, 11% men with diabetes were found to have hypogonadotropic hypogonadism in a study done by Ganesh et al.^[12]

Table 1.

Indian data on percentage prevalence of hypogonadism in subjects with Type 2 diabetes mellitus

Year	Author	N	%Prevalence of Hypogonadism	Total Testosterone	Free Testosterone	ADAM
2009	Ganesh et al.^[12]	100	15%		<64.8 pg/mL	Androgen deficiency symptoms questionnaire
2017	SV Madhu et al.^[13]	150	T2DM subjects without CAD-32%, T2DM subjects with CAD-40%.	<300 ng/dl
2017	Agarwal et al.^[14]	900	20.7%		<0.255 nmol/L	Yes
2020	Anupam et al.^[15]	150	17.3%		<6.3 ng/dl	Yes
2021	Gangwar SK et al.^[16]	130	26.9%	<300 ng/dl		Yes
2024	Unnikrishnan et al.^[17]	526	8.6%	Yes <300 ng/dl		Yes

Diabetes and Gonadal Function: A Possible Bidirectional Link

Ever since the discovery of this high prevalence of hypogonadism in diabetes, studies have tried to establish the mechanistic link. The question of whether hypogonadism is the cause or consequence in a person with diabetes has been an ongoing debate. The following discussion in this chapter focuses on hypogonadism in T2DM, obesity and the insulin resistance spectrum. It is important for a clinician to remember that a male (especially of younger age) with diabetes may have other aetiologies that may have direct or indirect links to hypogonadism. For instance, Type 1 diabetes may be part of autoimmune polyendocrinopathy syndrome (APS 1 or 2) affecting gonads also. Similarly, hemochromatosis may cause diabetes and hypogonadism due to common iron overload related glandular dysfunction (pituitary or testis). Alcohol may cause both testicular dysfunction and chronic pancreatitis-related secondary diabetes. Congenital conditions like Klinefelter syndrome and cystic fibrosis are also associated with primary hypogonadism and infertility. A detailed discussion of these conditions is not dealt with here.

Effect of Diabetes and Obesity on Gonadal Function

Inflammatory mediators (e.g., tumour necrosis factor-alpha [TNF-a] and interleukin-1beta [IL-1b]) can suppress hypothalamic and pituitary hormones (gonadotropin-releasing hormone [GnRH] and LH) in vitro [Figure 1].^[18,19] Insulin resistance reduces serum total testosterone by lowering the levels of sex hormone-binding globulin (SHBG).^[20] Leptin is known to stimulate GnRH neurons, further inducing LH release under normal circumstances. It has been observed that elevating the adipokine leptin in diabetic patients directly suppresses the effect of gonadotropins on the Leydig cells (testes) to decrease testosterone production. In obese diabetic patients, the resistance to leptin may further diminish androgen function.^[21,22] Aromatase activity in the adipose tissue of obese individuals leads to increased oestrogen secretion, which suppresses GnRH.^[23] Minor mechanisms like increased glucocorticoid turnover and the dysregulation of the hypothalamic-pituitary-gonadal axis, leading to hypoandrogenism and altered function of leukocytes due to microvascular disruption in the testes, might also contribute.^[24,25]

Figure 1.

Mechanisms of hypogonadism in males with Type 2 diabetes mellitus

Effect of Hypogonadism and Diabetes

Meta-analysis has shown that men with decreased testosterone levels have an increased tendency to develop T2DM.^[26] The main hypothesis proposed is that of central obesity and a higher degree of insulin resistance in individuals with low testosterone.^[27] The other mechanism is the low level of GLUT4 in myocytes and adipocytes as a result of low testosterone. This leads to reduced transport of glucose and reduced insulin sensitivity, leading to T2DM.^[28,29] Finally, abnormalities in the metabolism of lipids and altered body composition with increased central adiposity lead to diabetes.^[30]

Why Should Clinicians Be Concerned About Hypogonadism in Diabetes?

In a patient with co-existing hypogonadism and diabetes mellitus, metabolic consequences extend beyond sexual health. Low testosterone levels in men are associated with increased CV and metabolic risk factor burden, which translates to increased prevalence of dyslipidaemia and atherosclerosis.^[31,32] Various studies have shown that subnormal testosterone is associated with an increased incidence of CV events. Laughlin et al. showed that the hazard ratio for all-cause mortality was 1.44 and 1.36 for CV mortality in men with hypogonadism.^[33] Another study—Osteoporotic Fracture in Men (MrOS)—a Swedish cohort of 3014 men (mean age, 75 years; mean follow-up, 4.5 years) showed a 65% mortality risk in men with low Free T levels (6.1 ng/dl).^[34] Low levels of Free T are associated with a 69% risk of stroke or transient ischemic attack.^[35] Hypogonadal men with diabetes have a reduced haematocrit than those with normal testosterone levels.^[36] Hypogonadism is clear risk factor for osteoporosis (decreased bone mineral density), altered trabecular bone structure and increased fracture rate among men with diabetes.^[37-39]

Evaluation of Hypogonadism in a Patient with Diabetes (Box 1)

Clinical features of hypogonadism are often vague in men with T2DM. Poor glycaemic control and underlying comorbidities might also contribute to fatigue, lethargy and reduced exercise capacity. ED is the most commonly reported symptom. It is reported in 30% men with T2DM and functional hypogonadism.^[6] More often than not, ED in men with T2DM is not due to testosterone deficiency. It is often secondary to poor glycaemic control, peripheral vascular and autonomic nervous system involvement.^[40] Underlying hypogonadism is indicated by decrease in libido and decrease in early morning erections.

Box 1.

Evaluation of hypogonadism in a patient with diabetes

A careful history is important to confirm the diagnosis of hypogonadism to determine whether they have other medical comorbidities, history of head injury, cerebrovascular accident, intra cranial neoplasms or pituitary surgery, chronic illnesses (CKD/CLD), toxic exposure, substance abuse, concomitant medications that can cause hypogonadism, or co-existing subfertility. Also, history starting from delay in puberty, early morning erection, shaving frequency, sexual history, symptoms of loss of smell, any prior testicular disease, excessive exercise should also be elicited. A history of recent fracture after trivial trauma might give a clue to chronic testosterone deficiency-related severe osteoporosis.

Physical examination includes examination of testes (size/consistency), the distribution and amount of body hair and changes in fat distribution. Post-pubertal testosterone deficiency does not affect penile length. Normal penile size, normal or small soft testes, regression of pubic and axillary hair regression, normal body proportions and decreased shaving frequency indicate post-pubertal hypogonadism, and organic causes other than diabetes should be ruled out. Any history of liver disease and skin pigmentation can give a clue to underlying hemochromatosis. Dysmorphism and cardiac malformation can point towards RASopathies. An assessment of the prostate either clinically or by sonogram and measuring prostate-specific antigen (PSA) are vital for obtaining clues for hypogonadism and monitoring testosterone therapy if planned. Intellectual changes, mood and cognition should also be assessed.^[41]

Should We Measure Testosterone Levels in All Males with T2DM?

International societies like the American Association of Clinical Endocrinology (AACE) and American Diabetes Association (ADA) recommend checking levels of testosterone in diabetic patients with BMI > 30 kg/m² because of the mechanistic link between obesity, diabetes and hypogonadism. But this is not possible in day-to-day practice as men are usually not willing to disclose sexual symptoms. IDEA consensus guideline (2021) recommends measuring serum testosterone levels in men with T2DM with features (signs/symptoms) suggestive of hypogonadism (reduced libido, reduced early morning penile tumescence and ED).^[42]

Total Versus Free Testosterone: Which Is Better for Clinical Assessment?

Total testosterone assay is easily available, accepted and cost-effective to perform. Despite the variation in ranges and methods, physicians can check with their local laboratories for the acceptable values in their clinical practice. But in a person with diabetes, this may be confounded, and the value might be low due to reduced SHBG levels. Especially in an aging male with diabetes, elevated SHBG can normalise the testosterone value falsely. In an elderly male presenting with signs of hypogonadism and a normal total testosterone level, the clinician can check levels of Free T or SHBG and calculate bioavailable testosterone. Hence, guidelines recommend the measurement of Free T in patients with T2DM.^[1,42]

It is difficult to check Free T by methods like equilibrium dialysis or ultrafiltration. These methods are largely unavailable but highly dependable. A radioimmunoassay for Free T is widely available but less reliable. As total testosterone and SHBG assays are readily available and cost-effective, calculating bioavailable testosterone might be a good alternative. Guidelines recommend using an equation based on SHBG, total testosterone and serum albumin. This can be alternatively used to calculate Free T where the estimation via equilibrium dialysis is not feasible.^[1]

Whichever method is chosen, early morning measurements (8 am) after withholding the confounding medications is the norm. Lower levels should prompt repeat measurements to confirm the result.

In patients with repeated low testosterone, it is advised to measure FSH, LH and prolactin. Elevated FSH and LH levels suggest a primary testicular cause, and low or normal levels indicate a hypothalamic or pituitary cause. It is mandatory to rule out organic causes of hypogonadism in men with T2DM, low testosterone and low/low normal FSH/LH. In such situations, it is mandatory to do a pituitary hormone profile along with serum Free T4 and an MRI of the pituitary (as untreated hypothyroidism often mimics hypogonadism). Diagnostic cut-offs include 2.3 ng/ml for the lower limit for total testosterone (with levels <1.5 ng/ml necessitating referral to endocrinologist) and Free T <46 pg/ml.^[43,44]

The androgen deficiency in aging male (ADAM) score is a widely used screening tool to identify men at risk for hypogonadism [Box 2]; it has a high sensitivity and a low specificity.^[45]

Box 2.

ADAM questionnaire

Treatment

Androgen replacement therapy at age-appropriate, gradually escalating doses according to standard protocols is warranted for testosterone deficiency either due to hypo- or hypergonadotropic hypogonadism, especially in younger males. Monitoring is both clinical and biochemical, and the usual target is to maintain testosterone levels in the normal adult ranges. However, administering testosterone in a male with diabetes for primarily improving metabolic parameters like insulin resistance and dysglycaemia or lipid parameters alone is as yet controversial. Few studies have shown improvement in testosterone levels with a significant reduction in weight (more than 10%) by the patient (reversal of functional hypogonadism) following strict lifestyle measures or bariatric procedures.^[46] With potent incretin-based therapies (semaglutide and tirzepatide) showing nearly bariatric intervention like weight loss, obese males with significant comorbidities like hypogonadism may be ameliorated by the use of the latter agents.^[47]

Testosterone Therapy in Patients with Diabetes

With regards to testosterone replacement treatment (TRT) in hypogonadal patients with T2DM, the Endocrine Society (USA) recommends that testosterone therapy should not be used as a means of improving glycaemic control in men with T2DM with low testosterone concentrations.^[1] An Indian consensus group suggested the use of testosterone replacement in men with T2DM and functional hypogonadism (serum total testosterone <2.3 ng/ml; <8 nmol/l) with sexual dysfunction after discussing the risks versus benefits. A therapeutic trial of testosterone replacement can be considered in the same group in borderline cases (serum total testosterone: 2.3–3.5 ng/ml) with symptoms.^[42]

Testosterone is available in multiple forms: intramuscular injections, gel, patch, tablets or subcutaneous implantable pellets. If initiated, choice of testosterone formulation can be individualised (cost/ease of use, availability), etc. Transdermal testosterone gel was the most effective treatment for hypogonadal men with T2DM.^[42] However, in an Indian setting, due to tropical weather-related sweating and other skin issues and cost, the latter mode of administration of testosterone is seldom popular.

However, most of the guidelines uniformly recommend monitoring of testosterone administration related adverse effects. Breast and prostate cancer are absolute contraindications for testosterone replacement therapy. The Endocrine Society recommends that testosterone therapy should be avoided in men with PSA >4 ng/ml, unevaluated prostate nodule, severe lower urinary tract symptoms with benign enlargement of prostate hypertrophy, untreated heart failure, haematocrit >48% and chronic liver disease.^[1]

In spite of the above limitations and words of caution, there are potential benefits demonstrated in different clinical parameters related to testosterone treatment in patients with diabetes/metabolic syndrome including: glycaemic status, body composition (meta-analysis by Corona and colleagues),^[48] QOL (quality of life), sexual symptoms, cognition, mood etc. One significant concern among clinicians regarding testosterone treatment is its potential adverse effect on haematocrit with attendant thrombotic consequences and CV health.

Effect on Glycaemic Control

Trials on the benefits of testosterone therapy on glycaemic control in T2DM patients with functional hypogonadism have yielded mixed results. The discrepancy between various studies mostly reflects the small sample size, differences in age, BMI, testosterone measurements/cut-offs, baseline HbA1c levels, degrees/measures of insulin resistance, and use of oral hypoglycaemic agents.

In the TIMES-2 study (testosterone [transdermal] replacement in hypogonadal men with either metabolic syndrome or T2DM), the investigators found improvement in CV risk factors such as insulin resistance, cholesterol, lipoprotein (a), body fat composition, and sexual function only in patients with metabolic syndrome but not diabetes.^[49] Interventional studies showed a positive effect of TRT on insulin resistance and glycaemic status.^[49]

Four landmark studies of testosterone replacement therapy in men with late onset hypogonadism have been published recently: (a) TEAAM, (b) TRAVERSE, (c) T4DM, (d) T-TRIALS and the salient points related to the trials are tabulated in Table 2.

Table 2.

Landmark trials on testosterone replacement therapy^[50–54]

Trial Name	Testosterone Levels	Objective	Glucose Metabolism	Bone	Haematocrit	CV Events	Limitations
TEAAM N = 308 ≥ 60 years	Serum total T 3.47–13.9 nmol/L	Carotid artery intimal thickness and coronary artery calcium scores	NA	NA	NA	No increase in progression of carotid intimal thickness or coronary artery calcium scores	CV subset underpowered to detect a difference
T-Trials N = 790 Greater than 65 years Seven sub-studies	Serum total Testo ≤ 9.5 nmol/L + symptoms or signs of testo deficiency	Sexual activity. Physical function. Vitality. Cognitive function. Haemoglobin. Bone mineral density of the spine. Volume of non-calcified coronary artery plaque	Significant decrease of fasting insulin/HOMA-IR. No change in plasma fasting glucose. Decreased serum total, LDL, HDL cholesterol	Significant increase in bone mineral density of lumbar spine	54% in the Testo arm had a significant increase in haemoglobin ≥1.0 g/dL	Increase in volume of non-calcified plaque. No effect on mace	CV subset underpowered to detect a difference
T4DM N = 1007 50–74 years of age Patients with impaired glucose tolerance or newly diagnosed Type 2 diabetes	Serum total T ≤ 14 nmol/L	Prevention or reversion of Type 2 diabetes as defined by a two-year serum two-hour glucose of ≥200 mg/dl on oral glucose tolerance test	Greater reduction in fasting glucose in T vs. placebo group No effect on HbA1c TRT reduced the presence of T2DM by 40% compared to placebo 0.4 kg gain of muscle mass 4.6 kg fat loss in treated arm	Significant increase of tibial bone mineral density, increased bone mineral density at the lumbar spine (3.3%), total hip (1.9%) and femoral neck (1.7%)	NA	NA	CV subset underpowered to detect a difference
Traverse N = 5246 45–80 years Pre-diabetes (n = 1175) or Diabetes (n = 3880),	Serum total T 3.5–10.4 nmol/L + symptoms or signs of testosterone deficiency. 70% T2DM/45% CAD	Composite of major cardiovascular adverse event (non-fatal myocardial infarction, non-fatal stroke or cardiovascular death)	Over a mean follow-up of 32 months, Testo therapy compared to placebo did not reduce rates of progression of prediabetes		15% more men receiving T had r esolution of anaemia at six months. 24 (0.9%) men—pulmonary embolism	Increased non-fatal cardiac arrhythmias (mostly atrial fibrillation). 7% primary MACE. Therapy noninferior to placebo in respect to MACE (HR 0.96)	60% discontinuation rate is a limiting factor

T-Trials and TRAVERSE showed a negligible effect on markers of insulin resistance or glycaemic control. Whereas the most recent T4DM offers a whopping 40% risk reduction in the development of T2DM. It offers not only proof of the bidirectional link between DM and hypogonadism but also a new therapeutic option in combination with lifestyle modification for diabetes remission.

Effect on CV Health

TEAAM, T-Trials and T4DM trials showed very low rates of major adverse cardiovascular events (MACE), but these studies were underpowered in that they failed to detect a difference. The TRAVERSE trial was a primary CVOT trial. However, the major limitation was 60% discontinuation rate. There was higher incidence of pulmonary embolism, arrhythmias (non fatal/atrial fibrillation) requiring intervention and acute kidney injury among patients who received testosterone.

Hence, treatment with testosterone should be individualised after assessing and explaining the risks versus benefits.

Summary and Take Home Points

Testosterone deficiency is recognised to be increasingly prevalent in men with the spectrum of metabolic syndrome (central obesity to prediabetes to diabetes). Among Indian men with T2DM, studies have shown a prevalence of confirmed testosterone deficiency in up to 10%-15%. From a clinician’s point of view, whenever erectile/sexual dysfunction is considered in a male with diabetes, it is prudent to thoroughly examine the patient for clinical clues of hypoandrogenemia as well as its aetiology (hypothalamo-pituitary vs. primary testicular causes). For patients with diabetes and clearly documented hypogonadism, both clinically, biochemically and etiologically, there is little or no controversy in replacement therapy with age-appropriate doses of testosterone. However, in diabetes patients with low normal testosterone values or subjects with symptoms suggestive of androgen deficiency but normal testosterone, option of testosterone replacement is still controversial. Multiple studies have shown the benefits of testosterone replacement by different parameters. However, concerns still remain regarding safety of long-term testosterone therapy with respect to occult prostate malignancy, rise in haematocrit and its thrombotic consequences including CV events. The risks versus benefits of testosterone replacement therapy in diabetes patients needs to be clarified by long-term follow-up studies. Thus, currently, clinicians have to be aware of the strong association between low testosterone and diabetes and the possible benefits; however, they exercise their clinical judgement and caution to individualise whom to screen for hypogonadism and replace with testosterone.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Institutional Ethical Committee Approval Number

Not applicable..

Informed consent

No patients are involved in this review article.

Credit author statement

Both authors have contributed equally to reviewing the literature, discussion points, writing, corrections and re-reviewing manuscript.

Data availability

Not applicable.

Use of artificial intelligence

Nil.

References

Bhasin

, Brito

, Cunningham

, . Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2018 May 1;103(5):1715–44. doi: 10.1210/jc.2018-00229

Salonia

, Rastrelli

, Hackett

, . Paediatric and adult-onset male hypogonadism. Nat Rev Dis Primers. 2019 May 30;5(1):38. doi: 10.1038/s41572-019-0087-y

Cho

, Shaw

, Karuranga

, . IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018 Apr;138:271–81. doi: 10.1016/j.diabres.2018.02.023

Dandona

, Dhindsa

. Update: hypogonadotropic hypogonadism in Type 2 diabetes and obesity. J Clin Endocrinol Metab. 2011 Sep;96(9):2643–51. doi: 10.1210/jc.2010-2724

Grossmann

, Thomas

, Panagiotopoulos

, . Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008 May;93(5):1834–40. doi: 10.1210/jc.2007-2177

Dhindsa

, Prabhakar

, Sethi

, Bandyopadhyay

, Chaudhuri

, Dandona

. Frequent occurrence of hypogonadotropic hypogonadism in Type 2 diabetes. J Clin Endocrinol Metab. 2004;89:5462–8.

Barrett-Connor

, Khaw

, Yen

. Endogenous sex hormone levels in older adult men with diabetes mellitus. Am J Epidemiol. 1990 Nov;132(5):895e901.

Grossmann

, Matsumoto

. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management. J Clin Endocrinol Metab. 2017;102:1067–75. doi: 10.1210/jc.2016-3580

Rhoden

, Ribeiro

, Teloken

, Souto

. Diabetes mellitus is associated with subnormal serum levels of free testosterone in men. BJU Int. 2005;96:867–70.

10.

Dhindsa

, Furlanetto

, Vora

, Ghanim

, Chaudhuri

, Dandona

. Low estradiol concentrations in men with subnormal testosterone concentrations and Type 2 diabetes. Diabetes Care. 2011 Aug;34(8):1854–9.

11.

Kumar

, Malhotra

, Jacob

. Targeting testosterone measurements to patients with Type 2 Diabetes and moderate to severe symptomatic erectile dysfunction. Diabetes Res Clin Pract. 2018 Mar;137:221e3.

12.

Ganesh

, Vijaya

Sarathi AH

, George

, . Prevalence of hypogonadism in patients with Type 2 diabetes mellitus in an Asian Indian study Group. Endocr Pract. 2009;15(6):513e20.

13.

Madhu

, Aslam

, Aiman

, Siddiqui

, Dwivedi

. Prevalence of hypogonadism in male Type 2 diabetes mellitus patients with and without coronary artery disease. Indian J Endocrinol Metab. 2017 Jan-Feb;21(1):31–7.

14.

Agarwal

, Singh

, Chowdhury

, . A study to evaluate the prevalence of hypogonadism in Indian males with Type-2 diabetes mellitus. Indian J Endocrinol Metab. 2017;21(1):64e70.

15.

Anupam

, Shivaprasad

, Vijaya

, Sridevi

, Aiswarya

, Nikhil

. Prevalence of hypogonadism in patients with Type 2 diabetes mellitus among the Indian population. Diabetes Metab Syndr. 2020 Sep-Oct;14(5):1299–304.

16.

Gangwar

, Verma

, Modi

. Frequency and correlates of hypogonadism in adult males with Type 2 diabetes mellitus. Indian J Endocrinol Metab. 2021 Jul-Aug;25(4):320–5.

17.

Unnikrishnan

, Saboo

, Majumdar

, . Association between Type 2 diabetes and hypogonadism in India: an observational study. Indian J Endocrinol Metab. 2024 Sep-Oct;28(5):473–9.

18.

Watanobe

, Hayakawa

. Hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, mediate the endotoxin-induced suppression of the reproductive axis in rats. Endocrinology. 2003 Nov;144(11):4868–75.

19.

Russell

, Small

, Stanley

, Franks

, Ghatei

, Bloom

. The in vitro role of tumour necrosis factor-alpha and interleukin-6 in the hypothalamic-pituitary gonadal axis. J Neuroendocrinol. 2001 Mar;13(3):296–301.

20.

Kaplan

, Crawford

. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care. 2006 Mar;29(3):749.

21.

Gamba

, Pralong

. Control of GnRH neuronal activity by metabolic factors: the role of leptin and insulin. Mol Cell Endocrinol. 2006;254-255:133–9. doi: 10.1016/j.mce.2006.04.023

22.

Pasquali

. Obesity and androgens: facts and perspectives. Fertil Steril. 2006;85(5):1319e40.

23.

Dhindsa

, Furlanetto

, Vora

, Ghanim

, Chaudhuri

, Dandona

. Low estradiol concentrations in men with subnormal testosterone concentrations and Type 2 diabetes. Diabetes Care. 2011 Aug;34(8):1854–9.

24.

Stewart

, Boulton

, Kumar

, Clark

, Shackleton

. Cortisol metabolism in human obesity: impaired cortisone/cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab. 1999;84:1022e7.

25.

Pitteloud

, Hardin

, Dwyer

, . Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab. 2005;90:2636e41.

26.

Yao

, Wang

, An

, Zhang

, Ding

. Testosterone level and risk of Type 2 diabetes in men: a systematic review and meta-analysis. Endocr Connect. 2018;7(1):220–31.

27.

Rao

, Kelly

, Jones

. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nat Rev Endocrinol. 2013;9:479e93.

28.

Mitsuhashi

, Senmaru

, Fukuda

, . Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes. Endocrine. 2016;51:174e84.

29.

Sato

, Iemitsu

, Aizawa

, Ajisaka

. Testosterone and DHEA activate the glucose metabolism-related signalling pathway in skeletal muscle. Am J Physiol Endocrinol Metab. 2008;294(5):E961-8.

30.

Chakrabarti

, Kandror

. The role of mTOR in lipid homeostasis and diabetes progression. Curr Opin Endocrinol Diabetes Obes. 2015;22:340e6.

31.

Haring

, Baumeister

, Völzke

, . Prospective association of low total testosterone concentrations with an adverse lipid profile and increased incident dyslipidemia. Eur J Cardiovasc Prev Rehabil. 2011;18:86–6.

32.

Svartberg

, von Mühlen

, Mathiesen

, Joakimsen

, Bønaa

, Stensland-Bugge

. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med. 2006;259:576–82.

33.

Laughlin

, Barrett-Connor

, Bergstrom

. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68–5.

34.

Tivesten

, Vandenput

, Labrie

, . Lowserum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94:2482–8.

35.

Yeap

, Hyde

, Almeida

, . Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J Clin Endocrinol Metab. 2009;94:2353–9.

36.

Bhatia

, Chaudhuri

, Tomar

, Dhindsa

, Ghanim

, Dandona

. Low testosterone and high C-reactive protein concentrations predict low hematocrit in Type 2 diabetes. Diabetes Care. 2006 Oct;29(10):2289–94.

37.

Orwoll

, Klein

. Osteoporosis in men. Endocr Rev. 1995 Feb;16(1):87–116.

38.

Benito

, Gomberg

, Wehrli

, . Deterioration of trabecular architecture in hypogonadal men. J Clin Endocrinol Metab. 2003;88:1497–502.

39.

Mellstro¨m

, Johnell

, Ljunggren

, . Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. J Bone Miner Res. 2006;21:529–35.

40.

Fedelo

, Bortolotti

, Carllo

, . On behalf of gruppo italiano studio deficit erettile nei diabetici. Erectile dysfunction in Type 1 and Type 2 diabetics in Italy. Int J Epidemiol. 2000;29:524e31.

41.

Carnegie

. Diagnosis of hypogonadism: clinical assessments and laboratory tests. Rev Urol. 2004;6(Suppl 6):S3-8.

42.

Majumdar

, Mukherjee

, Ray

, . Testosterone replacement therapy in men with Type 2 diabetes mellitus and functional hypogonadism—an Integrated Diabetes and Endocrine, Academy (IDEA) consensus guideline. Diabetes Metab Syndr. 2021 Jul-Aug;15(4):102191.

43.

Wang

, Nieschlag

, Swerdloff

, . Consensus statement: investigation, treatment and monitoring of late-onset hypogonadism in males - ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol. 2008;159:507e14.

44.

Morales

, Bebb

, Manjoo

, . Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. CMAJ. 2015 Dec 8;187(18):1369–77.

45.

Tancredi

, Reginster

, Schleich

, . Interest of the androgen deficiency in aging males (ADAM) questionnaire for the identification of hypogonadism in elderly community-dwelling male volunteers. Eur J Endocrinol. 2004;151(3):355e60.

46.

Khoo

, Piantadosi

, Worthley

, Wittert

. Effects of a low-energy diet on sexual function and lower urinary tract symptoms in obese men. Int J Obes. 2010;34:1396e403.

47.

Corona

, Rastrelli

, Monami

, . Body weight loss reverts obesity associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol. 2013;168:829e43.

48.

Corona

, Giagulli

, Maseroli

, . Therapy of endocrine disease: testosterone supplementation and body composition: results from a meta-analysis study. Eur J Endocrinol. 2016 Mar;174(3):R99-116.

49.

Jones

, Arver

, Behre

, . TIMES2 investigators. Testosterone replacement in hypogonadal men with Type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2010;34:828e37.

50.

Kumari

, Kumar

, Memon

, . Treatment with testosterone therapy in Type 2 diabetic hypogonadal adult males: a systematic review and meta-analysis. Clin Pract. 2023 Mar 20;13(2):454–69.

51.

Huang

, Wharton

, Bhasin

, . Effects of long-term testosterone administration on cognition in older men with low or low-to-normal testosterone concentrations: a prespecified secondary analysis of data from the randomised, double-blind, placebo-controlled TEAAM trial. Lancet Diabetes Endocrinol. 2016;4(8):657–65.

52.

Snyder

, Bhasin

, Cunningham

, . Testosterone trials investigators. Effects of testosterone treatment in older men. N Engl J Med. 2016 Feb 18;374(7):611–24.

53.

Wittert

, Bracken

, Robledo

, . Testosterone treatment to prevent or revert Type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. Lancet Diabetes Endocrinol. 2021;9(1):32–45.

54.

Lincoff

, Bhasin

, Flevaris

, . Traverse study investigators. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023 Jul 13;389(2):107–17.

Diabetes and Hypogonadism in Males

Abstract

Objectives:

Methodology:

Results:

Conclusions:

Keywords

Introduction

Epidemiology

Diabetes and Gonadal Function: A Possible Bidirectional Link

Effect of Diabetes and Obesity on Gonadal Function

Mechanisms of hypogonadism in males with Type 2 diabetes mellitus

Effect of Hypogonadism and Diabetes

Why Should Clinicians Be Concerned About Hypogonadism in Diabetes?

Evaluation of Hypogonadism in a Patient with Diabetes (Box 1)

Evaluation of hypogonadism in a patient with diabetes

Should We Measure Testosterone Levels in All Males with T2DM?

Total Versus Free Testosterone: Which Is Better for Clinical Assessment?

ADAM questionnaire

Treatment

Testosterone Therapy in Patients with Diabetes

Effect on Glycaemic Control

Effect on CV Health

Summary and Take Home Points

Footnotes

Declaration of conflicting interests

Funding

Institutional Ethical Committee Approval Number

Informed consent

Credit author statement

Data availability

Use of artificial intelligence

References